This proposal seeks funding for the development of an Alzheimer's disease (AD) therapeutic using an innovative approach to develop a pharmaceutical that can be used as both a treatment and as a preventative. AD is a devastating common disorder affecting primarily elderly people with a frequency of 5% of the population over 65, increasing to 20% over 80 and 50 % over 85 years of age. An estimated 14 million people in the world have the disease, at a cost of $100 billion per year in the United States. The prevalence and the cost continue to escalate with the increase in the mean age of the population. Currently, there is no cure for AD, and treatments are palliative rather than treating the underlying causes of the disease. An over production of beta-amyloid (Abeta), a natural occurring peptide processed from beta-amyloid precursor protein (APP), is the key element in the development of AD. Factors influencing over-production of Abeta increase the prevalence and early onset of Alzheimer's. Most current drug development programs are focused on altering the activities of the processing enzymes to cause a reduction in Abeta. These processing enzymes, however, are also involved in other important biological processes. A change in processing activity is likely to lead to undesired side effects. In a novel approach, we propose to identify a small molecule compound from a unique natural product source that alters APP conformation and processing to reduce the abundance of Abeta. The evidence that certain genetic mutations in APP alter conformation and processing leading to early onset of Alzheimer's disease without any other apparent health problems predicts that a therapeutic that alters APP conformation and processing would have a low risk of side effects. This type of pharmaceutical would have high utility not only for treatment of AD but also as a prophylactic for those at risk of developing the disease.